Neuroscience Blog

The antipsychotic haloperidol (Haldol) improves learning, while an agent that works similarly to other antipsychotics slows learning in monkeys.

Highlights

• An antipsychotic called haloperidol blocks certain neuronal receptors—D2 receptors—and significantly improves learning.
• Conversely, an agent that works similarly to other antipsychotics called SCH-23390 blocks a different type of neuronal receptor—D1 receptors—and significantly slows learning.

Dopamine is a neurotransmitter in the brain that plays key roles in cognitive processes such as memory, motivation, and decision-making. Interestingly, dysfunctional dopamine signaling is believed to play a critical role in cognitive impairment in patients with schizophrenia. To alleviate aberrant cognition in patients with schizophrenia, researchers have designed medications that modulate dopamine signaling, namely, drugs that block specific dopamine receptors—D1 and D2 receptors. However, how medications that target either of these receptors impact learning abilities has remained unclear.

Now, published in the Journal of Neuroscience, Russ and colleagues from the Icahn School of Medicine at Mount Sinai in New York show that an antipsychotic medication called haloperidol, which blocks D2 dopamine receptors, significantly improves learning in monkeys. Conversely, an antipsychotic that blocks D1 receptors called SCH-23390 significantly slows learning. Additionally, haloperidol increases connections, measured statistically, between brain regions associated with learning, and SCH-23390 reduces them. These findings suggest that haloperidol may improve learning and increase statistically measured connections between brain regions associated with learning.

Haloperidol’s invention, which occurred in 1958, made this antipsychotic a pioneering medication for use in patients with schizophrenia. Intriguingly, some patients with schizophrenia still currently use the drug.

Haloperidol’s mechanism of action to alleviate cognitive dysfunction in patients with schizophrenia is believed to be through blocking D2 dopamine receptors. Other antipsychotics like clozapine are thought to work by binding to D1 dopamine receptors in a way similar to SCH-23390 (which has not been approved as an antipsychotic). Accordingly, disentangling differences between antipsychotics that block either D1 or D2 receptors, specifically, their effects on learning, has become paramount.

Haloperidol Improved Learning while SCH-23390 Slowed Learning

To find how these two different types of antipsychotics affect learning, Russ and colleagues trained monkeys on a learning task. For each round of the learning task, the monkeys were allowed to choose between one of two visual stimuli by directing their visual attention toward it. The stimuli presented in each round were randomly selected from three visual stimuli associated with distinct reward probabilities—90%, 50%, and 30%. The reward for gazing at a certain stimulus was a drop of fruit juice.

Following injections of either of the antipsychotics blocking dopamine receptors, Russ and colleagues found certain effects on learning of visual stimulus-reward associations. In that sense, haloperidol significantly increased the correct performance in rounds where monkeys were getting familiar with and learning associations between visual stimuli and juice reward probabilities. Conversely, SCH-23390 significantly reduced the monkeys’ performance during these rounds. These results suggest that agents that block either D1 or D2 receptors, in this case, SCH-23390 or haloperidol, respectively, have opposing effects on learning.

In an attempt to uncover whether there is any correlation between these two antipsychotics’ effects on cognition and brain activity, Russ and colleagues analyzed how the medications influenced statistically measured connectivity between brain regions. The researchers found that while haloperidol enhanced statistically measured connectivity between brain structures associated with learning, SCH-23390 reduced this connectivity. These findings support the notion that haloperidol may improve learning by increasing connections between brain regions associated with learning.

Difficulty Teasing Out Whether Haloperidol Improves Learning in Patients with Schizophrenia

Altogether, this study using monkeys without any known underlying neurological conditions suggests that haloperidol may enhance certain aspects of cognition, such as learning. However, whether the findings with monkeys translate to patients with schizophrenia remains questionable. In that sense, schizophrenia is a debilitating disease that frequently severely impairs aspects of cognition like learning abilities, such that 80% to 90% of patients with schizophrenia remain unemployed for most of their adult lives. Due to the more rapid cognitive decline in many patients with schizophrenia compared to neurotypical individuals, it may prove very challenging to ascertain whether haloperidol recapitulates improvements in learning in human patients with schizophrenia.

Story Source

Fujimoto A, Elorette C, Fujimoto SH, Fleysher L, Rudebeck PH, Russ BE. Pharmacological modulation of dopamine receptors reveals distinct brain-wide networks associated with learning and motivation in non-human primates. J Neurosci. 2024 Dec 27:e1301242024. doi: 10.1523/JNEUROSCI.1301-24.2024. Epub ahead of print. PMID: 39730205.

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